Infection with the human immunodeficiency virus (HIV) results in progressive deterioration of the immune system in most infected subjects. During disease progression, key cells associated with the immune system become infected with HIV, including, e.g., CD4+ T cells, macrophages/monocytes, and glial cells. Prolonged HIV infection frequently culminates in the development of AIDS. In the late stages of this disease, the immune system is severely compromised due to loss or dysfunction of CD4+ T cells (Shearer et al. (1991) AIDS 5:245–253).
HIV-1-specific CD8+ cytotoxic T lymphocytes appear to be critical in the immunologic control of HIV-1 soon after the acquisition of infection. CTL precursors specific for cells expressing several HIV-1 gene products, including Gag, Pol, and Env antigens, are detectable within three weeks of the primary infection syndrome (Koup et al. (1994) J. Virol. 68:4650–4655). Since CTL activity is antigen driven, the waning in responding T-cell subsets that generally occurs with the passage of time is not unexpected. The clinical significance of this cellular immune response to HIV has been demonstrated in a number of studies, and impairment of this response appears to be associated with more rapid disease progression. Lymphokines elaborated by HIV-specific CD4+ T-cells are critical in supporting the genesis of these mature cytotoxic T lymphocytes directed against HIV-1 (Rosenberg et al. (1997) Science 278:1447–1450), lending credence to the notion that virus-specific T-helper cells are necessary for maintenance of effective immunity to HIV.
Anti-retroviral drugs, such as reverse transcriptase inhibitors, viral protease inhibitors, and viral entry inhibitors, have been used to treat HIV infection (Caliendo et al. (1994) Clin. Infect. Dis. 18:516–524). More recently, treatment with combinations of these agents, known as highly active antiretroviral therapy (HAART), has been used to effectively suppress replication of HIV (Gulick et al. (1997) N. Engl. J. Med. 337:734–9 (see comments); Hammer et al. (1997) N. Engl. J. Med. 337:725–733). However, HAART is primarily efficacious with regard to the prevention of the spread of infection into uninfected cells. This therapy cannot efficiently reduce the residual, latent proviral DNA integrated into the host cellular genome (Wong et al (1997) Science 278:1291–1295 (see comments); Finzi et al. (1997) Science 278:1295–1300 (see comments); Finzi et al. (1999) Nat. Med. 5:512–517; Zhang et al. (1999) N. Engl. J. Med. 340:1605–1613).
Anecdotal reports of individuals who have discontinued HAART have revealed a rapid relapse of viremia, most often within a few weeks of ceasing anti-viral therapy (Ruiz et al. (2000) AIDS 14:397–403). Consequently, HAART must be administered indefinitely to prevent reactivation of latent virus. Continuous treatment with HAART is problematic, as HAART regimens are expensive, are difficult to comply with, and have many side effects. In addition, prolonged treatment with antiretroviral agents often leads to the emergence of drug resistant viral strains (Larder et al. (1989) Science 246:1155–1158; Kellam et al. (1992) Proc. Natl. Acad. Sci. USA 89:1934–1938; St. Clair et al. (1991) Science 253:1557–1559). The emergence of drug-resistant viral strains is delayed with combination treatment aimed at different points in the HIV replication cycle (D'Aquila (1994) Clin. Lab. Med. 14:393–422). However, a significant portion of patients treated with combination therapy may eventually harbor strains of HIV having multi-drug resistance (Schinazi et al. (1994) Int. Antiviral News 2:72–5).
Recombinant human interleukin-2 (IL-2) has been studied in the setting of HIV disease for over a decade. This immunobiologic agent, when administered intermittently by either the SC or CIV route in conjunction with antiretroviral therapy, produces prominent and sustained increases in the CD4+ T-cell count in the vast majority of HIV-infected patients who have been recently studied (Kovacs et al. (1996) N. Engl. J. Med. 335:1350–1356; Davey et al. Abstract 689, ICAAC (San Francisco, Calif.), September, 1999; Arno et al. (1999) JID 180:56–60; Carr et al. (1998) J. Infect. Dis. 178(4):992–999; Hengge et al. (1998) AIDS 12:F225–F234; Levy et al. (1999) Lancet 353:1923–1929). The increase in the CD4+ T-cell compartment is polyclonal and is characterized by the genesis of CD4+ T-cells that are functional in vitro (Levy et al. (1999) Lancet 353:1923–1929).
Intermittent cycles of IL-2 produce transient rises in plasma viral load in some HIV-infected subjects (Davey et al. (1997) J. Infect. Dis. 175:781–789), however no controlled trials have demonstrated a deleterious long-term effect on viral burden. Indeed, several recent studies indicate IL-2 might have an antiviral effect (Davey et al. (1999) J. Infect. Dis. 179:849–858). The reason an antiviral effect of IL-2 has been observed only in several recent studies might relate to the higher sensitivity of the assays employed and/or the use of HAART.
In vitro data have shown that the IL-2 responsiveness of CD4+ cells of subjects well controlled virologically on HAART is greater than that of cells culled from patients with suboptimal virologic control. However, cessation of HAART in patients receiving cycles of IL-2 therapy in the past frequently leads to virologic rebound (Davey et al. (1999) Abstract 689, ICAAC (San Francisco, Calif.), September, 1999).
Given the problems associated with prolonged treatment with HAART and the tendency for rapid viral rebound following cessation of this combination therapy, even in patients receiving IL-2 therapy in the past, better methods are needed to achieve long-term immunologic control of HIV.